Lipophilic curcumin analogs and methods of inhibiting HIV-1, treating latent HIV in the brain, and preventing HIV-mediated cognitive decline and HIV dementia

ABSTRACT

Compounds having formulas (I) to (VIII), salts thereof, or combinations thereof and pharmaceutical compositions comprising one or more these compounds are described herein for the treatment of HIV and neurodegenerative effects caused by HIV. Also provided herein are methods and a kit for inhibiting HIV-1, treating latent HIV in the brain, and preventing HIV-mediated cognitive decline and HIV dementia comprising administering the compounds having the formulas (I) to (VIII) and pharmaceutical compositions comprising the compounds having these formulas. The compounds having formulas I through VIII are curcumin analogs which are advantageously characterized as having anti-retroviral, neuroprotective, anti-glucosidase, and anti-HIV integrase properties. In one aspect, the pharmaceutical composition is delivered intranasally.

This application claims the benefit of U.S. Provisional Application Ser.No. 61/756,892, filed Jan. 25, 2013, which is incorporated as if fullyrewritten herein and U.S. Provisional Application Ser. No. 61/684,316,filed Aug. 17, 2012 which also is incorporated herein as if fullyrewritten.

FIELD

This application relates to curcumin analogs and to pharmaceuticalcompositions containing them. Methods of inhibiting HIV-1, treatinglatent HIV in the brain, and methods of preventing HIV-mediatedcognitive decline and HIV dementia are also provided.

BACKGROUND

Acquired Immune Deficiency Syndrome (AIDS) remains one of the leadingcauses of morbidity and mortality in the world. In 2011, the UnitedNations reported that 1.7 million people died from AIDS-relatedillnesses. According to the United Nations Programme on AIDS, it wasestimated that, as of 2011, 34.2 million people worldwide were infectedwith human immunodeficiency virus (HIV), including 2.5 million peoplenewly infected with HIV in 2011. amfAR, the Foundation for AIDsResearch, reported that more than 60 million people have contracted HIVand approximately 30 million people have died of HIV-related causessince the epidemic began.

AIDS deaths reportedly have fallen for five years in a row, down from2.3 million in 2005 and 2006 to 1.7 million in 2011. With the successfulcurtailment of the proliferation of HIV in the blood through theintroduction of highly-active antiretroviral therapy (HAART), thepopulation of people infected with HIV now live longer, which has led tothe emergence of latent HIV brain infections and associated cognitivedecline as a major public health threat. However, current HAARTtreatment does not treat latent HIV brain disease. HIV is known to crossthe blood-brain barrier and enter the nervous system early in systemicinfection. It has been reported that neurologic disease is the firstmanifestation of symptomatic HIV infection in many patients, and thatthe majority of patients with advanced HIV disease have clinicallyevident neurologic dysfunction. Numerous neurological complications areassociated with AIDS, including AIDS dementia complex (ADC), which isalso known as HIV-associated dementia (HAD), HIV encephalopathy, andHIV-associated neurocognitive disorder.

Curcumin, a natural product isolated from the rhizome of Curcuma longa,has been investigated as a possible HIV treatment. Curcumin hasdemonstrated a wide range of biological activity, including antioxidant,anti-inflammatory, and anticancer. (Du et al., European J. MedicinalChemistry, 41:213-218 (2006).) Curcumin also inhibits the enzymealpha-glucosidase and HIV integrase, which are required by HIV-1 toinfect human cells. However, clinical studies of curcumin for HIVtreatment have produced unsatisfactory results, which are believed to bedue, at least in part, to the rapid metabolism of orally administeredcurcumin by the liver into metabolites that are inactive and incapableof crossing the blood-brain barrier to become available to the brain(Anand et al. 2007). As such, curcumin does not have the ability toreach the brain in sufficient quantities and duration to protect thebrain from HIV-1 toxicity.

In addition, curcumin is poorly absorbable by mouth because it is notvery lipophilic (Anand et al. 2007). Animal studies have largely reliedon intraperitonial (i.e., injecting inside the abdomen) and intracranial(i.e., injecting into the brain) administrations to achieve biologicaleffects that are seen in in vitro (i.e., direct tissue) treatments.Moreover, previous in vitro studies of curcumin for HIV inhibition haveshown that larger concentrations of curcumin (i.e., in micrograms) areneeded to exact pharmacological action.

Therefore, a need remains for a composition that is administrablethrough routes that are feasible for daily human use for HIV treatmentand that can reach the brain site for prevention of direct and indirectHIV-mediated toxicity.

SUMMARY

Provided herein are lipophilic curcumin analogs having formulas (I) to(VIII) or pharmaceutical acceptable salts thereof and pharmaceuticalcompositions comprising one or more of these curcumin analogs havingformulas (I) to (VIII) or pharmaceutical acceptable salts thereof. Alsoprovided are methods for treating latent HIV in the brain and preventingHIV-mediated cognitive decline and HIV dementia comprising administeringthese analogs and/or pharmaceutical compositions comprising one or morelipophilic curcumin analogs having any of formulas (I) to (VIII) orpharmaceutical acceptable salt thereof to a subject adversely affectedby HIV in the brain and/or cognitive decline. In another aspect, amethod is provided for inhibiting HIV-1 replication, the methodcomprising inhibiting HIV-1 with one or more curcumin analog having anyof formulas (I) to (VIII) or pharmaceutical acceptable salt thereof.

Advantageously, the curcumin analogs described herein also demonstrateenhanced solubility or dispersibility in non-aqueous solvents, such aschlorofluorohydrocarbons, which are commonly used as propellants inintranasal drug delivery systems. Such solubility, dispersibility andlipophilicity mean that the compounds or analogs described herein havethe potential to reach the brain more easily to protect it against HIVtoxicity. While not wishing to be bound by theory, it is presentlybelieved that the curcumin analogs described herein protect brain cellsthrough stimulating increased levels of neuroprotective factors (e.g.,brain-derived neurotrophic factor (“BDNF”)) and through increasingsurvival of neurons.

In a very important aspect, the analogs or pharmaceutical compositionsdescribed herein are in suitable form for intranasal delivery. Whendelivered intranasally, the analog can be absorbed systemically, therebyavoiding massive liver metabolism which affects the natural curcumincompound. In one aspect, the curcumin analog or pharmaceuticalcomposition is dissolved or dispersed and provided in an olfactoryneuroplastic device for direct delivery to the brain through theolfactory mucosa in the nose. In yet another very important aspect, theolfactory neuroplastic device is illustrated in the drawings herein.That device may be used to administer the compounds and pharmaceuticalcompositions which include other agents (such as odorants or otherantiviral agents) for the treatment of neurodegenerative diseases. A kitwhich includes intranasal delivery of one or more compounds of formula Ithrough VIII or pharmaceutical compositions which include one or more ofthese compounds is also described herein.

In another form, the pharmaceutical compositions and methods describedherein may further comprise not only compounds or compositions for thetreatment of neurodegenerative diseases but also at least one otherantiviral agent effective to inhibit viral replication in a subject foruse in combination therapy. Exemplary antiviral agents for use incombination therapy include, for example antiretroviral agents such asnucleoside reverse transcriptase inhibitors, nonnucleoside reversetranscriptase inhibitors, protease inhibitors, integrase inhibitors,fusion inhibitors, and chemokine receptor antagonists.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of an exemplary intranasal delivery devicesuitable for administration of the curcumin analogs described herein.

FIG. 2 is a nuclear magnetic resonance spectra (NMR) of the curcuminanalog having formula I.

FIG. 3 is a chart showing the anti-HIV action of curcumin analog havingformula I compared to curcumin.

FIG. 4 is a chart showing the effects of curcumin and curcumin analoghaving formula I on AKT1, BDNF and MAPK1 in CEM cells.

DETAILED DESCRIPTION

Provided herein are lipophilic curcumin analogs having the molecularstructure of formulas (I) to (VIII) or pharmaceutically acceptable saltsthereof and pharmaceutical compositions comprising one or more of theseanalogs having the structure of formulas (I) to (VIII) or pharmaceuticalacceptable salts thereof. These analogs are advantageously characterizedby having anti-retroviral, neuroprotective, anti-glucosidase, andanti-HIV integrase properties. These properties make the analogsuniquely suitable as a treatment for neuroAIDS and latent brain HIVdisease, as well as for prophylaxis against HIV-mediated cognitivedecline and dementia.

Methods for treating latent HIV in the brain and preventing HIV-mediatedcognitive decline and HIV dementia are also described herein. Thesemethods comprise administering to a subject in need thereof an effectiveamount of any of the compounds of formulas (I) to (VIII),pharmaceutically acceptable salts thereof, or combination thereof and/ora pharmaceutical composition comprising one or more of these compoundsor salts thereof. In another aspect, a method is provided for inhibitingHIV-1 replication, the method comprising administering one or morecompounds of any of formulas (I) to (VIII), pharmaceutically acceptablesalts thereof, or combination thereof, including administering apharmaceutical composition which includes one or more of the compoundsand/or pharmaceutically acceptable salts in an amount which is effectivefor inhibiting HIV-1 replication.

Advantageously, the curcumin analogs (compounds having formulas Ithrough VIII) described herein also demonstrate enhanced solubility ordispersibility in non-aqueous solvents, such aschlorofluorohydrocarbons, which are commonly used as propellants inintranasal drug delivery systems. Such solubility and lipophilicitymeans that the analogs described herein have the potential to reach thebrain more easily to protect it against HIV toxicity. While not wishingto be bound by theory, it is presently believed that the curcuminanalogs described herein protect brain cells through stimulatingincreased levels of neuroprotective factors (e.g., BDNF) and throughincreasing survival of neurons in the brain.

Because of its enhanced lipophilic properties, the compounds having theformulas provided herein are uniquely suitable for intranasal andsublingual drug delivery. As used herein, “salt” means anypharmaceutically acceptable metal substitute for hydrogen on a phenolichydrogen or complexed with the formulas described herein.“Pharmaceutically acceptable salt” as used herein means a salt suitablefor use in a mammal without undue toxicity or adverse response. Thepharmaceutical compositions may also comprise other actives forneurodegenerative diseases as well as conventional excipients, solvents,and/or carriers, if desired.

As used herein, “alkyl” includes straight or branched chain alkyl having1 to 3 carbons, including for example, methyl, ethyl, n-propyl,isopropyl, and the like. Generally “halogen” includes F, Br, I, or Cl,but preferably is F.

The term “aryl” includes phenyl, optionally substituted at one or morepositions with alkyl having 1 to 3 carbons or halogen.

As used herein, lipophilicity refers to the affinity of a compound for alipophilic environment. By one approach, lipophilicity can be determinedusing an octanol-water partition coefficient (K_(ow)), which representsthe ratio of the solubility of a compound in octanol (a non-polarsolvent) to its solubility in water (a polar solvent). The higher theK_(ow), the more non-polar the compound. Log K_(ow) values are generallyinversely related to aqueous solubility and directly proportional tomolecular weight. For purposes herein, lipophilicity values rangebetween 0 to 10 and a value of at least 2.5 indicates goodlipophilicity. A log K_(ow) value less than 0 is considered hydrophilic.

One curcumin analog is(1E,4E)-1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one (MW326.34), which may be formulated and used as described above. Thisanalog was found to be very lipophilic. It has the structure of formula(I):

The compound of formula (I) was synthesized by removal of enolizableprotons of curcuma. This analog has demonstrated superiority overcurcumin for inhibition of HIV-1 virus in vitro at nanomolarconcentration levels. The removal of enolizable protons was found toaugment the lipophilic character of curcumin while enhancing itsbiological activity (including antiretroviral and neuroprotection). Itwas found that the compound of formula (I) is able to inhibit HIV at thenanomolar level. This makes the compound a particularly suitabletreatment for neuroAIDS and latent HIV brain disease.

A curcumin analog having formula II and pharmaceutical composition whichcomprises a compound of formula (II) below may be formulated and used asdescribed above:

each X is independently selected from H, CH, or halogen (preferably thehalogen is F), and n=1 to 5, wherein if n=1 a three membered ring isdefined, if n=2 a four membered ring is defined, if n=3 a five memberedring is defined, if n=4 a six membered ring is defined and if n=5 aseven membered ring is defined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons.

A curcumin analog having formula (III) and pharmaceutical compositionwhich comprises a compound of formula (III) below may be formulated andused as described above:

where

-   X is O, NH, S, or CH₂, and-   Y is O, NH, S, or CH₂.

A curcumin analog having formula IV and pharmaceutical composition whichcomprises a compound of formula IV below may be formulated and used asdescribed above:

n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a fourmembered ring is defined, if n=3 a five membered ring is defined, if n=4a six membered ring is defined and if n=5 a seven membered ring isdefined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons.

A curcumin analog and pharmaceutical composition which comprises acompound of formula (V) below may be formulated and used as describedabove:

where each X is independently selected from NH, O, or S.

A curcumin analog having formula (VI) and pharmaceutical compositionwhich comprises a compound of formula (VI) below may be formulated andused as described above:

where

-   R₁=alkyl (preferably lower alkyls of 1 to 3 carbons) or phenyl which    may be substituted or unsubstituted at any position with halogen or    alkyl having 1-3 carbon atoms,-   R₂=halogen, ether, or thioether, and-   n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a    four membered ring is defined, if n=3 a five membered ring is    defined, if n=4 a six membered ring is defined and if n=5 a seven    membered ring is defined,    where carbons of the ring may include —CH or —CH₂ and wherein the    carbons of the ring optionally can be substituted with halogen or    alkyl having 1 to 3 carbons.

A curcumin analog having formula (VII) and pharmaceutical compositionwhich comprises a compound of formula (VII) below may be formulated andused as described above:

where

-   R₁=phenol, phenolic ether, thiophenol, thioether, halogen, or alkyl;-   R₂=phenol, phenolic ether, thiophenol, thioether, halogen, or alkyl;-   each R₃ is independently selected from H, halogen, phenol, and    phenolic ether; and-   R₄═H, halogen, phenol, or phenolic ether,-   n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a    four membered ring is defined, if n=3 a five membered ring is    defined, if n=4 a six membered ring is defined and if n=5 a seven    membered ring is defined,    where carbons of the ring may include —CH or —CH₂ and wherein the    carbons of the ring optionally can be substituted with halogen or    alkyl having 1 to 3 carbons.

A curcumin analog having formula (VIII) and pharmaceutical compositionwhich comprises a compound of formula (VIII) below may be formulated andused as described above:

where each R is independently selected from alkyl or phenyl, which mayoptionally be substituted at any position with halogen or alkyl having 1to 3 carbons,n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a fourmembered ring is defined, if n=3 a five membered ring is defined, if n=4a six membered ring is defined and if n=5 a seven membered ring isdefined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons.

The pharmaceutical composition includes an effective amount of one ormore curcumin analog having formulas (I) to (VIII) or a pharmaceuticallyacceptable salt of these compounds. By “effective amount” is meant atherapeutically justified or a prophylactically justified amount of theanalog. A therapeutically justified amount is the amount of the analogneeded to provide a desired biological or medical response in a subject,while a prophylactically justified amount is the amount of the analogneeded to prevent, suppress, or slow progress of HIV-mediated cognitivedecline and HIV dementia in a subject infected with HIV. In oneparticular aspect, the subject is a mammal and in another aspect is ahuman.

The curcumin analogs described herein and pharmaceutical compositionscomprising these curcumin analogs can be administered to a subject inneed thereof in at a dosage determined upon factors known to one skilledin the art, such as but not limited to timing and route ofadministration, frequency of treatment, activity of the analog, healthof the subject, including weight, age, severity of HIV infection, andthe like.

The compounds of formulas (I) to (VIII), pharmaceutically acceptablesalts thereof and pharmaceutical compositions which include thesecompounds are effective for inhibiting HIV-1 replication. A method isprovided for inhibiting HIV-1 replication comprising administering thesecompounds, pharmaceutically acceptable salts thereof, or combinationsthereof which may be part of the pharmaceutical composition in effectiveamounts to inhibit HIV-1 replication.

In another aspect, the compounds of formulas (I) to (VIII),pharmaceutically acceptable salts thereof and pharmaceuticalcompositions which include these compounds are effective for preventingHIV-mediated cognitive decline and HIV dementia. In this aspect, amethod also is provided comprising administering to a subject in need oftreatment at least one of these compounds, pharmaceutically acceptablesalts, or combinations thereof which may be a part of the pharmaceuticalcomposition in an amount effective to prevent HIV mediated cognitivedecline and/or dementia.

In yet another aspect, the compounds of any of formulas (I) to (VIII),pharmaceutically acceptable salt thereof and pharmaceutical compositionscomprising one or more of these compounds are effective for treatinglatent HIV in the brain. In this aspect, a method also is providedcomprising administering to a subject in need of treatment of latent HIVin the brain at least one of these compounds of formulas (I) to (VIII),pharmaceutically acceptable salts, or combinations thereof.

As used herein, a subject in need of treatment has tested positive forHIV infection in the past and may have achieved undetectable levels ofHIV in the blood (through usual treatment for HIV) but may still haveeither dormant HIV virus in the brain or HIV-associated immune reactionsaffecting the brain, with resultant impairment in brain functions (e.g.,cognitive decline, mood problems, personality changes or psychosis).

It is also presently believed that the compounds of formulas (I) to(VIII) have anti-hepatitis C activity. A method for treating hepatitis Cis also provided, the method comprising administering to a subject inneed of treatment at least one of these compounds, pharmaceuticallyacceptable salts, or combinations thereof which may be a part of thepharmaceutical composition in an amount effective to prevent HIVmediated cognitive decline and/or dementia. A subject in need ofhepatitis C treatment has tested positive for hepatitis C infection.

The compounds of formulas (I) to (VIII) or pharmaceutical compositionscomprising them as described herein can be applied systemically orlocally. The compounds or compositions may be associated with or coatedonto nanoparticles for systemic or local administration. Thenanoparticles may range in size of from about 10,0000 nanometers to assmall as 1 nanometer. The particles may be polymeric, such aspolyethylene glycol, albumin, and biocompatible styrene.

In one particularly important aspect, the compounds of formulas (I) to(VIII) and pharmaceutical compositions which include such compounds orpharmaceutically acceptable salts are formulated for intranasaladministration. Administration via non-oral routes (e.g., parenteralroutes) may avoid hepatic first pass metabolism but result in theanalogs being distributed systemically and requiring the analogs have tocross the blood-brain barrier to get into the brain. However, theintranasal administration is one parenteral route that may have lesssystemic distribution and could reach the brain directly through theolfactory nerve in the nose, avoiding the blood-brain barrier. Suchintranasal administration may be through a device which pushes thecompositions into the olfactory mucoca of the nose by positive airpressure via a device as described herein. Alternatively suchadministration may be by nasal spray which carries the activecompositions into contact with the olfactory mucoca.

In the aspect where the treatments are intranasally administered, thecompounds of formulas (I) to (VIII), pharmaceutically acceptable salts,and pharmaceutical compositions comprising one or more of them can beabsorbed systemically, thereby avoiding massive liver metabolism whichaffects the natural curcumin compound. In one aspect, the curcuminanalog is dissolved and provided in an olfactory neuroplastic device fordirect delivery to the brain through the olfactory mucosa in the nose.

An exemplary intranasal delivery device is shown in FIG. 1. Theapparatus includes cannula 2 having a conduit 4 into a chamber 6 whichholds the active ingredient. In one approach, the active ingredient is acurcumin analog provided herein. Pump 10 pumps air at a positivepressure through conduit 12 to filter 14 and flow meter 16 past checkvalve 18 into chamber 6. The air under positive pressure sweeps theactive ingredient from the chamber 6 into conduit 4 and pushes theactive ingredient through cannula 2 into the nose of the user. By oneapproach, the device may be powered by electricity through a 9V adapterplugged to any electrical source, such as a wall outlet. By anotherapproach, the device is portable to permit treatment at locations andtimes convenient to the subject undergoing treatment. In this aspect,the device is operated with DC current being supplied by a battery andthe device has a housing to accommodate the battery. The device mayoptionally further include an outlet to recharge the battery shouldrechargeable batteries be used.

In the aspect where the compounds and pharmaceutical compositions areintranasally delivered or administered, the compounds and compositionsdescribed are provided in the intranasal delivery device in an amountsuitable for a determined treatment regimen, such as for example basedon suitable animal models.

In another form, the pharmaceutical compositions and methods describedherein may further comprise at least one other antiviral agent effectiveto inhibit viral replication in a subject for use in combinationtherapy. Exemplary antiviral agents for use in combination therapyinclude, for example antiretroviral agents such as nucleoside reversetranscriptase inhibitors, nonnucleoside reverse transcriptaseinhibitors, protease inhibitors, integrase inhibitors, fusioninhibitors, and chemokine receptor antagonists. The pharmaceuticalcompositions and methods described herein may also further comprise atleast one other agent for treating neurodegenerative diseases.

In yet another form, a packaged pharmaceutical composition is providedwhich includes instructions for use of the composition for inhibitingHIV-1, treating latent HIV in the brain, and/or preventing HIV-mediatedcognitive decline and HIV dementia.

Advantages and embodiments of the methods and curcumin analogs describedherein are further illustrated by the following examples; however, theparticular conditions, processing schemes, materials, and amountsthereof recited in these examples, as well as other conditions anddetails, should not be construed to unduly limit this method. Allpercentages are by weight unless otherwise indicated.

EXAMPLES Example 1 Synthesis of Curcumin

A 50 mL round-bottomed flask was charged with boric oxide (1.75 g, 25.0mmole) suspended in DMF (5.0 mL). Acetylacetone (2.5 mL, 25.0 mmole) wasadded, followed by tributyl borate (13.5 mL, 50 mmole). The reactionmixture was warmed to 65° C. and 4-hydroxy-3-methoxybenzaldehyde(vanillin, 7.6 g, 50 mmole) was added followed by the addition of asolution of n-BuNH₂ (0.5 mL) and acetic acid (1.5 mL) in acetic acid(5.0 mL). The reaction mixture was heated to 95° C. for 4 hours. It wasslowly cooled to 10° C. It was diluted with ethyl acetate (100 mL)followed by the addition of HCl (1N, 250 mL). The reaction mixture washeated to 70° C. and was stirred for 1 hour. The brown solid thus formedwas isolated using vacuum filtration. It was thoroughly washed withwater and dried. Purification of the crude product using silica gelflash column chromatography (elution with 40% ethyl acetate in hexanes)afforded the desired product (4.1 g, 45% yield) as fluorescent yellowsolid. ¹H- and ¹³C-NMR data (FIG. 2) for the synthetic curcumin samplewas found to be consistent with previously reported literature.

Example 2 Synthesis of Curcumin Analog

Glacial acetic acid (10 mL) was saturated with anhydrous hydrogenchloride and was cooled to 0° C. Vanillin (1.52 g, 10 mmole) and acetone(370 μL, 5 mmole) was added and the reaction mixture was stirred at 0°C. for 30 minutes. It was slowly warmed to room temperature and stirredat room temperature for an additional 48 hours. The crude reactionmixture was poured into ice cold water (100 mL). The crude product waswashed and dried. The purification by silica gel flash columnchromatography (elution with 1% MeOH in CH₂Cl₂) resulted in theisolation of the curcumin analog. ¹H- and ¹³C-NMR data for the curcuminanalog was found to be consistent with previously reported literature.

Example 3 Antiretroviral Activity of Curcumin Analogs

The antiretroviral activity of the analog of Example 2 was analyzed inCEM T cells infected with vesicular stomatitus virus glycoprotein (VSVG)pseudotyped HIV-1 pNL 4-3 virus expressing luciferase (VSVG-HIV-1 Luc)and treated with various concentrations of the curcumin analog. Thecells were collected at 48 hours post infection, and luciferase activitywas analyzed with Luclite Kit (Perkin Elmer) using Labsystems LuminoscanRT equipment (Perkin Elmer). The novel curcumin analog displayed apotent anti-HIV activity with IC50 of 8 nM (FIG. 3). Moreover, theanalog also displayed a wider therapeutic index (IC50:cytotoxicityratio) as compared to curcumin. Enhanced lipophilicity appears to be animportant factor in the superior biological activity displayed by thecurcumin analog.

Example 4 Curcumin Analogs

Curcumin analogs in accordance with the description herein can beprepared having the structures shown below in Table 1:

TABLE 1

Compound 12 Compound 13 Compound 14 Compound 15 n = 1 n = 2 n = 3 n = 4

Compound 16 Compound 17 Compound 18 Compound 19 n = 1 n = 2 n = 3 n = 4

Compound 20 Compound 21 Compound 22 Compound 23 n = 1 n = 2 n = 3 n = 4

Compound 24 Compound 25 Compound 26 Compound 27 n = 1 n = 2 n = 3 n = 4

Compound 28 Compound 29 Compound 30 Compound 31 n = 1 n = 2 n = 3 n = 4

Compound 32 Compound 33 Compound 34 Compound 35 n = 1 n = 2 n = 3 n = 4

Compound 36 Compound 37 Compound 38 X = NH X = O X = S

Compound 39   Compound 40   Compound 41 R1 = alkyl; R2 = halogen R1 =aryl; R2 = ether R1 = alkyl; R2 = thioether wherein if n = 1 a threemembered ring is defined, if n = 2 a four membered ring is defined, if n= 3 a five membered ring is defined, if n = 4 a six membered ring isdefined.

Example 4 Effects of Curcumin and a Curcumin Analog on mRNA Levels ofBDNF, AKT1, and MAPK1

Along with brain-derived neurotrophic factor (“BDNF”), protein kinase B(“AKT”), and mitogen-activated protein kinase 1 (“MAPK1”) (i.e., ERK1/2)genes are known to critically regulate cell survival and growth ofneurons during development and the survival and function of adultneurons, as well as modulate synaptic transmission and plasticity. Thisexample compares activities of natural curcumin and curcumin analog(1E,4E)-1,5-bis(4-hydroxy-3-methoxyphenyl)penta-1,4-dien-3-one on AKT,MAPK1 and ERK. The analog was predicted to be more biologically soluble,absorbable, and more resistant to degradation than the natural curcumin.It has already been shown that natural curcumin increases the expressionof BDNF in the hippocampus of rats. It was believed that, compared tonatural curcumin, the analog would result in greater increase in theactivities of these three neuroprotective genes as proof-of-principle ofneuroprotection from latent HIV brain disease. The analysis wasconducted on CEM cell lines, which are cells that are susceptible to HIVinfection.

The results are shown in FIG. 4. As shown, curcumin analog significantlyincreased the mRNA level in AKT1, BDNF and MAPK1. Natural curcuminresulted in a slight increase in AKT and MAPK1 mRNA level butsurprisingly resulted in a decrease in the BDNF mRNA level.

It will be understood that various changes in the details, materials,and arrange-ments of the process, formulations, and ingredients thereof,which have been herein described and illustrated in order to explain thenature of the method and resulting curcumin analogs and pharmaceuticalcompositions, may be made by those skilled in the art within theprinciple and scope of the embodied method as expressed in the appendedclaims.

What is claimed is:
 1. A method for treating cognitive decline in asubject having HIV, wherein the cognitive decline is mediated by thedecrease of BDNF mRNA levels in the brain, the method comprisingadministering to a subject infected with HIV at least one compound ofany of formulas (I) to (VIII), a pharmaceutically acceptable saltthereof, or combination thereof amount in a therapeutically effectiveamount to increase BDNF mRNA levels in the brain:

each X is independently selected from H, CH₃, or halogen, and n=1 to 5,wherein if n=1 a three membered ring is defined, if n=2 a four memberedring is defined, if n=3 a five membered ring is defined, if n=4 a sixmembered ring is defined and if n=5 a seven membered ring is defined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons;

where X is O, NH, S, or CH₂, and Y is O, NH, S, or CH₂;

n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a fourmembered ring is defined, if n=3 a five membered ring is defined, if n=4a six membered ring is defined and if n=5 a seven membered ring isdefined, where carbons of the ring may include —CH or —CH₂ and whereinthe carbons of the ring optionally can be substituted with halogen oralkyl having 1 to 3 carbons;

where each X is independently selected from NH, O, or S;

where R₁=alkyl or phenyl which may be substituted or unsubstituted atany position with halogen or alkyl having 1-3 carbon atoms, R₂=halogen,ether, or thioether, and n=1 to 5, wherein if n=1 a three membered ringis defined, if n=2 a four membered ring is defined, if n=3 a fivemembered ring is defined, if n=4 a six membered ring is defined and ifn=5 a seven membered ring is defined, where carbons of the ring mayinclude —CH or —CH₂ and wherein the carbons of the ring optionally canbe substituted with halogen or alkyl having 1 to 3 carbons;

where R₁=phenol, phenolic ether, thiophenol, thioether, halogen, oralkyl; R₂=phenol, phenolic ether, thiophenol, thioether, halogen, oralkyl; each R₃ is independently selected from H, halogen, phenol, andphenolic ether; and R₄=H, halogen, phenol, or phenolic ether, n=1 to 5,wherein if n=1 a three membered ring is defined, if n=2 a four memberedring is defined, if n=3 a five membered ring is defined, if n=4 a sixmembered ring is defined and if n=5 a seven membered ring is defined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons;

where each R is independently selected from alkyl or phenyl, which mayoptionally be substituted at any position with halogen or alkyl having 1to 3 carbons, n=1 to 5, wherein if n=1 a three membered ring is defined,if n=2 a four membered ring is defined, if n=3 a five membered ring isdefined, if n=4 a six membered ring is defined and if n=5 a sevenmembered ring is defined, where carbons of the ring may include —CH or—CH₂ and wherein the carbons of the ring optionally can be substitutedwith halogen or alkyl having 1 to 3 carbons; and salt thereof, orcombination thereof.
 2. The method according to claim 1, wherein the atleast one compound of any of formulas (I) to (VIII) is intranasallyadministered.
 3. The method according to claim 1, wherein the at leastone compound of any of formulas (I) to (VIII) form a part of apharmaceutical composition which further comprises an antiviral agentother than at least one compound of formulas (I) to (VIII).
 4. Themethod according to claim 3, wherein the antiviral agent is selectedfrom the group consisting of nucleoside reverse transcriptaseinhibitors, nonnucleoside reverse transcriptase inhibitors, proteaseinhibitors, integrase inhibitors, fusion inhibitors, chemokine receptorantagonists, and combinations thereof.
 5. The method according to claim1, wherein the at least one compound of any of formulas (I) to (VIII) isdispersed into a pharmaceutically acceptable oil.
 6. The methodaccording to claim 1, wherein the at least one compound of any offormulas (I) to (VIII) form a part of a pharmaceutical composition whichis associated with nanoparticles and is intranasally administered. 7.The method according to claim 1, wherein the at least one compound ofany of formulas (I) to (VIII) form a part of a pharmaceuticalcomposition which is associated with nanoparticles.
 8. The methodaccording to claim 1, wherein R1 is a lower alkyl of 1 to 3 carbons. 9.The method according to claim 1, wherein the at least one compoundadministered to the subject comprises a compound of formula (I) or apharmaceutically acceptable salt thereof:


10. The method according to claim 9, wherein the compound of formula (I)or a pharmaceutically acceptable salt thereof is dispersed into apharmaceutically acceptable oil and the administering is by intranasaladministration.
 11. The method according to claim 1, wherein the atleast one compound administered to the subject comprises a compound offormula (II) or a pharmaceutically acceptable salt thereof:

each X is independently selected from H, CH₃, or halogen, and n=1 to 5,wherein if n=1 a three membered ring is defined, if n=2 a four memberedring is defined, if n=3 a five membered ring is defined, if n=4 a sixmembered ring is defined and if n=5 a seven membered ring is defined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons.
 12. The method according to claim 11, wherein thecompound of formula (II) or a pharmaceutically acceptable salt thereofis dispersed into a pharmaceutically acceptable oil and theadministering is by intranasal administration.
 13. The method accordingto claim 1, wherein the at least one compound administered to thesubject comprises a compound of formula (III) or a pharmaceuticallyacceptable salt thereof:

where X is O, NH, S, or CH₂, and Y is O, NH, S, or CH₂.
 14. The methodaccording to claim 13, wherein the compound of formula (III) or apharmaceutically acceptable salt thereof is dispersed into apharmaceutically acceptable oil and the administering is by intranasaladministration.
 15. The method according to claim 1, wherein the atleast one compound administered to the subject comprises a compound offormula (IV) or a pharmaceutically acceptable salt thereof:

n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a fourmembered ring is defined, if n=3 a five membered ring is defined, if n=4a six membered ring is defined and if n=5 a seven membered ring isdefined, where carbons of the ring may include —CH or —CH₂ and whereinthe carbons of the ring optionally can be substituted with halogen oralkyl having 1 to 3 carbons.
 16. The method according to claim 15,wherein the compound of formula (IV) or a pharmaceutically acceptablesalt thereof is dispersed into a pharmaceutically acceptable oil and theadministering is by intranasal administration.
 17. The method accordingto claim 1, wherein the at least one compound administered to thesubject comprises a compound of formula (V) or a pharmaceuticallyacceptable salt thereof:

where each X is independently selected from NH, O, or S.
 18. The methodaccording to claim 17, wherein the compound of formula (V) or apharmaceutically acceptable salt thereof is dispersed into apharmaceutically acceptable oil and the administering is by intranasaladministration.
 19. The method according to claim 1, wherein the atleast one compound administered to the subject comprises a compound offormula (VI) or a pharmaceutically acceptable salt thereof:

where R₁=alkyl or phenyl which may be substituted or unsubstituted atany position with halogen or alkyl having 1-3 carbon atoms, R₂=halogen,ether, or thioether, and n=1 to 5, wherein if n=1 a three membered ringis defined, if n=2 a four membered ring is defined, if n=3 a fivemembered ring is defined, if n=4 a six membered ring is defined and ifn=5 a seven membered ring is defined, where carbons of the ring mayinclude —CH or —CH₂ and wherein the carbons of the ring optionally canbe substituted with halogen or alkyl having 1 to 3 carbons.
 20. Themethod according to claim 19, wherein R1 is a lower alkyl of 1 to 3carbons.
 21. The method according to claim 19, wherein the compound offormula (VI) or a pharmaceutically acceptable salt thereof is dispersedinto a pharmaceutically acceptable oil and the administering is byintranasal administration.
 22. The method according to claim 1, whereinthe at least one compound administered to the subject comprises acompound of formula (VII) or a pharmaceutically acceptable salt thereof:

where R₁=phenol, phenolic ether, thiophenol, thioether, halogen, oralkyl; R₂=phenol, phenolic ether, thiophenol, thioether, halogen, oralkyl; each R₃ is independently selected from H, halogen, phenol, andphenolic ether; and R₄=H, halogen, phenol, or phenolic ether, n=1 to 5,wherein if n=1 a three membered ring is defined, if n=2 a four memberedring is defined, if n=3 a five membered ring is defined, if n=4 a sixmembered ring is defined and if n=5 a seven membered ring is defined,where carbons of the ring may include —CH or —CH₂ and wherein thecarbons of the ring optionally can be substituted with halogen or alkylhaving 1 to 3 carbons.
 23. The method according to claim 22, wherein R1is a lower alkyl of 1 to 3 carbons.
 24. The method according to claim22, wherein the compound of formula (VII) or a pharmaceuticallyacceptable salt thereof is dispersed into a pharmaceutically acceptableoil and the administering is by intranasal administration.
 25. Themethod according to claim 1, wherein the at least one compoundadministered to the subject comprises a compound of formula (VIII) or apharmaceutically acceptable salt thereof:

where each R is independently selected from alkyl or phenyl, which mayoptionally be substituted at any position with halogen or alkyl having 1to 3 carbons, n=1 to 5, wherein if n=1 a three membered ring is defined,if n=2 a four membered ring is defined, if n=3 a five membered ring isdefined, if n=4 a six membered ring is defined and if n=5 a sevenmembered ring is defined, where carbons of the ring may include —CH or—CH₂ and wherein the carbons of the ring optionally can be substitutedwith halogen or alkyl having 1 to 3 carbons; and salt thereof, orcombination thereof.
 26. The method according to claim 25, wherein thecompound of formula (VIII) or a pharmaceutically acceptable salt thereofis dispersed into a pharmaceutically acceptable oil and theadministering is by intranasal administration.